JPH06145136A - Substituted benzenesulfonamide derivative - Google Patents

Abstract

PURPOSE:To obtain a new substituted benzenesulfonamide derivative, having antagonistic action on thromboxane A2 receptors well balanced with inhibiting action on thromboxane A2 synthesis in combination and useful as a blood plate let agglutination suppressor, an antithrombotic agent and an antiasthmatic agent. CONSTITUTION:This compound is expressed by formula I (R<1> is H, lower alkyl, lower alkoxy or halogen; R<2> is phenyl, thienyl or furyl which may respectively have a substituent group; R<3> is H or lower alkyl; (n) is 1-5) and its pharmacologically permissible salt, e.g. 4-[phenyl(phenylsulfonylamino)methyl] phenylacetic acid. This compound is obtained by reacting an amine derivative expressed by formula II with a sulfonyl chloride derivative expressed by formula III in a solvent in the presence of a base and, as necessary, hydrolyzing the resultant ester.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a substituted benzene sulfone having a thromboxane A ₂ receptor antagonistic action, a thromboxane A ₂ synthesis inhibitory action and the like and useful as a platelet aggregation inhibitor, antithrombotic agent and antiasthma agent. The present invention relates to an amide derivative and a pharmacologically acceptable salt thereof.

[0002]

Benzenesulfonamide derivatives having a thromboxane A ₂ receptor antagonistic action include, for example,
U.S. Pat. No. 4,258,058 has the following formula

[Chemical 2] Slotroban and the like are also disclosed in US Pat.
No. 477 has the following formula

[Chemical 3] Although daltroban represented by the formula (1) and the like are disclosed, no compound having a structure similar to that of the present invention has been known so far.

[0003]

[Problems to be Solved by the Invention] Thromboxane A
₂ is a powerful physiologically active substance biosynthesized from arachidonic acid in vivo, has a platelet aggregation action and a smooth muscle contraction action of the bronchus, coronary arteries, etc. Overproduction is believed to cause various disorders such as thrombosis and asthma.

Drugs that antagonize thromboxane A ₂ receptors with thromboxane A ₂ or thromboxane A _2
The drug that inhibits the synthesis of ₂ is a preventive agent against diseases caused by thromboxane A ₂ , for example, ischemic heart diseases such as angina and myocardial infarction, cerebrovascular disorders, thrombosis, and asthma. Alternatively, it can be expected to be useful as a therapeutic agent. or,
Thromboxane A ₂ receptor antagonism and thromboxane A
₍₂₎ Drugs that also have a synthetic inhibitory action are expected to have more reliable efficacy by enhancing both actions or a complementary effect.

At present, some thromboxane A ₂ receptor antagonists and thromboxane A ₂ synthesis inhibitors are in clinical trial stage, but few drugs have been put on the market, and further research is required.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in view of the aforementioned circumstances, the novel substituted benzenesulfonamide derivative according to the present invention was found to have a thromboxane A ₂ receptor antagonistic action and a thromboxane A. Not only does it have a well-balanced combination of ₂ synthetic inhibitors, but surprisingly it has leukotriene antagonism, prostaglandin antagonism, platelet activating factor (PAF) -induced airway stenosis inhibition, and immunoglobulin-mediated airway stenosis inhibition. ,
The inventors have found that they are extremely useful as platelet aggregation inhibitors, antithrombotic agents, and antiasthma agents, and completed the present invention.

That is, the present invention has the following general formula (I)

[Chemical 4] (In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, R ² is a phenyl group which may have a substituent, a thienyl group or a furyl group, and R ³ is a hydrogen atom or The present invention relates to a novel substituted benzenesulfonamide derivative represented by a lower alkyl group, n is an integer of 1 to 5) and a pharmacologically acceptable salt thereof.

In the above general formula (I) of the present invention, R ¹ and R
Examples of the lower alkyl group represented by ³ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group, and R ¹ Examples of the lower alkoxy group represented by are methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like, and halogen atom is Examples include fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Examples of the substituent which may be substituted on the phenyl group, thienyl group and furyl group represented by R ² include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and isobutyl group. , Lower-alkyl groups such as sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. Examples thereof include a lower alkoxy group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a lower alkyl group substituted with a halogen atom such as a fluoromethyl group, a difluoromethyl group and a trifluoromethyl group.

Preferred examples of the substituted benzenesulfonamide derivative of the present invention include the following compounds, but the present invention is not limited to these examples. (1) 4- [phenyl (phenylsulfonylamino) methyl] phenylacetic acid (2) 4- [phenyl (phenylsulfonylamino) methyl] methyl phenylacetate (3) 4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenylacetic acid (4) 4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] methyl phenylacetate (5) 3- [4- [phenyl (phenylsulfonylamino) methyl] phenyl] propionic acid (6) Methyl 3- [4- [phenyl [phenyl (phenylsulfonylamino) methyl] phenyl] propionate ( 7) Methyl 3- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] propionic acid (8) Methyl 3- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] propionic acid (9) 4 -[4- [Phenyl (phenylsulfonylamino) methyl] phenyl] butyric acid (10) Methyl 4- [4- [phenyl (phenylsulfonylamino) methyl] phenyl] butyrate (11) 4- [4-[(4-fluoro Phenyl) (phenylsulfonylamino) methyl] phenyl] butyric acid (1 ) Methyl 4- [4-[(4-fluorophenyl) (phenylsulfonylamino) methyl] phenyl] butyrate (13) 4- [4-[(4-Chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (14) 4 Methyl 4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyrate (15) Ethyl 4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyrate (16) 4- [4- [(4-Chlorophenylsulfonylamino) (2-fluorophenyl) methyl] phenyl]
Butyric acid (17) 4- [4-[(4-chlorophenylsulfonylamino) (2-fluorophenyl) methyl] phenyl]
Methyl butyrate (18) 4- [4-[(4-chlorophenylsulfonylamino) (3-fluorophenyl) methyl] phenyl]
Butyric acid (19) 4- [4-[(4-chlorophenylsulfonylamino) (3-fluorophenyl) methyl] phenyl]
Methyl butyrate (20) 4- [4-[(4-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Butyric acid (21) 4- [4-[(4-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Methyl butyrate (22) 4- [4-[(4-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Ethyl butyrate (23) 4- [4-[(4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl] phenyl] butyric acid (24) 4- [4-[(4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl ] Phenyl] methyl butyrate (25) 4- [4-[(4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl] phenyl] butyrate ethyl (26) 4- [4-[(4-chlorophenylsulfonylamino) (4 -Methylphenyl) methyl] phenyl] butyric acid (27) Methyl 4- [4-[(4-chlorophenylsulfonylamino) (4-methylphenyl) methyl] phenyl] butyrate (28) 4- [4-[(4-chlorophenyl Sulfonylamino) (2-methoxyphenyl) methyl] phenyl]
Butyric acid (29) 4- [4-[(4-chlorophenylsulfonylamino) (2-methoxyphenyl) methyl] phenyl]
Methyl butyrate (30) 4- [4-[(4-chlorophenylsulfonylamino) (4-methoxyphenyl) methyl] phenyl]
Butyric acid (31) 4- [4-[(4-chlorophenylsulfonylamino) (4-methoxyphenyl) methyl] phenyl]
Methyl butyrate (32) 4- [4-[(4-chlorophenylsulfonylamino) (4-trifluoromethylphenyl) methyl]
Phenyl] butyric acid (33) 4- [4-[(4-chlorophenylsulfonylamino) (4-trifluoromethylphenyl) methyl]
Phenyl] butyric acid methyl (34) 4- [4-[(4-fluorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (35) 4- [4-[(4-Fluorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid Methyl (36) 4- [4-[(4-fluorophenylsulfonylamino) phenylmethyl] phenyl] butyrate ethyl (37) 4- [4-[(4-fluorophenyl) (4-
Fluorophenylsulfonylamino) methyl] phenyl] butyric acid (38) 4- [4-[(4-fluorophenyl) (4-
Methyl fluorophenylsulfonylamino) methyl] phenyl] butyrate (39) 4- [4-[(4-fluorophenyl) (4-
Fluorophenylsulfonylamino) methyl] phenyl] ethyl butyrate (40) 4- [4-[(4-chlorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl]
Butyric acid (41) 4- [4-[(4-chlorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl]
Methyl butyrate (42) 4- [4-[(4-chlorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl]
Ethyl butyrate (43) 4- [4-[(4-Bromophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (44) 4- [4-[(4-Bromophenylsulfonylamino) phenylmethyl] phenyl] methyl butyrate ( 45) 4- [4-[(4-bromophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Butyric acid (46) 4- [4-[(4-bromophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Methyl butyrate (47) 4- [4-[(4-Methylphenylsulfonylamino) phenylmethyl] phenyl] butyric acid (48) Methyl 4- [4-[(4-methylphenylsulfonylamino) phenylmethyl] phenyl] butyrate ( 49) 4- [4-[(4-fluorophenyl) (4-
Methylphenylsulfonylamino) methyl] phenyl]
Butyric acid (50) 4- [4-[(4-fluorophenyl) (4-
Methylphenylsulfonylamino) methyl] phenyl]
Methyl butyrate (51) 4- [4-[(4-methoxyphenylsulfonylamino) phenylmethyl] phenyl] butyric acid (52) Methyl 4- [4-[(4-methoxyphenylsulfonylamino) phenylmethyl] phenyl] butyrate ( 53) 4- [4-[(4-fluorophenyl) (4-
Methoxyphenylsulfonylamino) methyl] phenyl] butyric acid (54) 4- [4-[(4-fluorophenyl) (4-
Methoxyphenylsulfonylamino) methyl] phenyl] methyl butyrate (55) 5- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] valeric acid (56) 5- [4-[(4-chlorophenylsulfonylamino) Phenylmethyl] phenyl] methyl valerate (57) 5- [4-[(4-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Valeric acid (58) 5- [4-[(4-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Methyl valerate (59) 6- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] hexanoic acid (60) 6- [4-[(4-Chlorophenylsulfonylamino) phenylmethyl] phenyl] hexanoic acid methyl ester (61) 4- [4-[(2-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (62) 4- [4-[(2-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid methyl (63) 4- [4-[(2-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Butyric acid (64) 4- [4-[(2-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Methyl butyrate (65) 4- [4-[(3-Chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (66) Methyl 4- [4-[(3-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyrate (67) 4- [4-[(3-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Butyric acid (68) 4- [4-[(3-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl]
Methyl butyrate (69) (-)-4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (70) (-)-4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid Methyl ( 71) (+)-4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid (72) (+)-4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid methyl (73) 4 -[4-[(4-Chlorophenylsulfonylamino) (2-thienyl) methyl] phenyl] butyric acid (74) Methyl 4- [4-[(4-chlorophenylsulfonylamino) (2-thienyl) methyl] phenyl] butyric acid ( 75) 4- [4-[(4-chlorophenylsulfonylamino) (2-thienyl) methyl] Phenyl] butyric acid ethyl (76) 4- [4-[(4-chlorophenylsulfonylamino) (2-furyl) methyl] phenyl] butyric acid (77) 4- [4-[(4-chlorophenylsulfonylamino) (2-furyl ) Methyl] phenyl] methyl butyrate

Of the compounds represented by the above general formula (I) of the present invention, those in which R ³ is a hydrogen atom may be converted into a pharmacologically acceptable salt, if necessary, or the formed salt. Can also be converted to the free acid.

Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention include alkali addition salts such as inorganic alkali salts such as sodium, potassium, calcium and ammonium, Alternatively, salts of organic bases such as trimethylamine, triethylamine, pyrrolidine, piperidine, piperazine, N-methylmorpholine and the like can be mentioned.

The compound represented by the general formula (I) of the present invention may have optical isomers based on asymmetric carbon,
The present invention includes any of these isomers and mixtures thereof.

The novel substituted benzenesulfonamide derivative represented by the above general formula (I) of the present invention can be produced by the following method, but the production method of the compound is not limited to these methods. Absent.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) has the following general formula (II):

[Chemical 5] (Wherein R ² , R ³ and n have the same meanings as described above) and the following general formula (III)

[Chemical 6] (In the formula, R ¹ has the same meaning as described above.) A sulfonyl chloride derivative represented by the above is reacted in a solvent in the presence of a base, and the ester is hydrolyzed if necessary. it can.

Any solvent may be used as a solvent for reacting the compound of the general formula (II) with the compound of the general formula (III), for example, diethyl ether, tetrahydrofuran, 1,4. -Ether solvents such as dioxane, chloroform, methylene chloride, 1,
Examples thereof include halogenated hydrocarbon solvents such as 2-dichloroethane, aromatic hydrocarbon solvents such as benzene and toluene, and aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide.

The base used in this reaction is
For example, organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene and pyridine, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate may be used. The reaction is carried out in the range of 0 ° C. to the reflux temperature of the solvent.

The ester hydrolysis reaction can be carried out by using a base or an acid in a water-containing solvent.

The water-containing solvent used in this reaction may be only water, but one mixed with a solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, tetrahydrofuran or 1,4-dioxane. Is preferred.

The base used in this reaction is
Examples thereof include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like, and examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. Reaction is 0
It is carried out in the range from ℃ to the reflux temperature of the solvent.

The amine derivative represented by the general formula (II) used as a starting material in the present production method is a novel compound and can be produced as follows. The details are described as a reference example in the examples.

[Chemical 7] (In the formula, R ² , R ³ and n have the same meanings as described above.)

The above-mentioned general formula (I) produced in this manner
The pharmaceuticals containing the novel substituted benzenesulfonamide derivative and a pharmacologically acceptable salt thereof as the active ingredient are usually capsules, tablets, fine granules, granules, powders,
It is administered as an oral administration agent such as a syrup or an injection. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, in the case of oral agents, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl methylcellulose,
Polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.) Solubilizers or solubilizers that can form the mold (distilled water for injection, physiological saline, propylene glycol, etc.), pH adjusters (inorganic or organic acids or bases), isotonic agents (salt,
Pharmaceutical components such as glucose and glycerin) and stabilizers are used.

The dose of the compound of the present invention to a patient to be treated depends on the patient's condition, but in the case of an adult, the daily dose is usually about 1 to 1000 mg by oral administration and 1 to 500 by parenteral administration.
It is about mg.

[0023]

The following is an example of the excellent action of the compound of the present invention: thromboxane A ₂ receptor antagonistic action, thromboxane A ₂ synthase inhibitory action, platelet aggregation inhibitory action, airway stenosis inhibitory action, leukotriene D ₄ antagonistic action. The test results of prostaglandin F ₂ α antagonistic action, immunoglobulin E-related asthma model improving action and acute toxicity are shown below. The following compounds were used as control drugs. Control drug: daltroban

Test Example 1 Thromboxane A ₂ receptor antagonism Guinea pig (about 400 g) 1/10 volume 3.8 from abdominal aorta
After collecting the sodium citrate blood, centrifuge the blood,
Platelet-rich plasma (PRP: 6 × 10 ⁵ cells / μl) was obtained. PRP 1
90 μl was placed in a cuvette, set in an aggregometer (Hematracer I; Nikko Bioscience), and 1 μl of a dimethyl sulfoxide solution of the test compound was added 37
Incubated at 0 ° C for 2 minutes. U-4661, which is an agonist of thromboxane A ₂ / prostaglandin H ₂ receptor in its PRP and has a strong platelet aggregation action
9 (Caymann) to a final concentration of 2 μg / ml 10
μl was added and platelet aggregation was measured with an aggregometer. Table 1 shows the 50% inhibitory concentration (IC ₅₀ value) against platelet aggregation.

[0025]

[Table 1] The compound of the present invention showed a superior thromboxane receptor antagonistic action as compared with the control drug.

Test Example 2 Thromboxane A ₂ synthase inhibitory action As a source of thromboxane A ₂ synthase, 285 μl of 100 μg / ml of commercially available human platelet membrane fraction (RAN) and 10 μl of a dimethyl sulfoxide solution of a test compound and prostaglandin H ₂ (Caymann) 100 μg / ml and 5 μl were mixed and reacted at 25 ° C. for 3 minutes. The stable thromboxane B ₂ of the generated thromboxane A ₂ was converted to the RIA method (TXB ₂
Quantitation kit; NEN). Table 2 shows the concentration at which the enzyme activity is suppressed by 50% (IC ₅₀ value).

[0027]

[Table 2] The compound of the present invention showed a superior thromboxane A ₂ synthase inhibitory action as compared with the control drug.

Test Example 3 Inhibitory Effect on Platelet Aggregation A test compound was orally administered to Hartley male guinea pigs (about 400 g), and one hour later, blood was collected from the abdominal aorta under ether anesthesia. Hereinafter, the treatment was carried out according to the method of Test Example 1. The results are shown in Table 3.

[0029]

[Table 3] The compound of the present invention showed an excellent inhibitory effect on platelet aggregation as compared with the control drug.

Test Example 4 Inhibition of airway stenosis Hartley male guinea pig (about 400 g) was dissolved in urethane (1.5 g).
/ kg, ip) after anesthesia with artificial respirator (Model 683; Harvar
(Company d) ventilating with a sensor (Model 7020; Ugo basile) to measure the amount of overflow exceeding 12 cmH ₂ O pressure.
Airway resistance was evaluated according to the method of nzett-Roessler.
The test compound was orally administered by suspending gum arabic in guinea pigs that had been fasted for 24 hours in advance, and 2 hours later, U-46619 (4 μg / kg) was administered into the jugular vein.
The value was measured 3 minutes after the reaction reached its maximum. The value was converted by regarding complete occlusion as 100%, and the same test was conducted at a plurality of doses to calculate a 50% inhibition value (ED ₅₀ value). The results are shown in Table 4.

[0031]

[Table 4] The compound of the present invention showed a superior airway stenosis suppressing effect as compared with the control drug.

Test Example 5 Leukotriene D ₄ Antagonistic Action Hartley male guinea pig ileum was excised in accordance with a conventional method to form a strip having a length of about 2 cm, and the strip was placed in a excision experimental tank filled with Tyrode's solution at 28 ° C. 0.5 g was suspended to be isotonic. Leukotriene D ₄ (1 × 10 ^-8 M; Salford Ult
When the contraction length becomes constant, the test compound is applied for 5 minutes in the coexistence of indomethacin (1 × 10 ⁻⁵ M; Sigma), and then leukotriene D ₄ (1 ×). The contraction length according to 10 ⁻⁸ M) was measured. Table 5 shows the 50% inhibition values (IC ₅₀ values) for the control group.

[0033]

[Table 5] The control drug did not show leukotriene D ₄ antagonism, but the compound of the present invention showed excellent leukotriene D ₄ antagonism.

Test Example 6 Prostaglandin F ₂ α Antagonistic Action Dogs (8 to 11 kg) were anesthetized with pentobarbital and exsanguinated from the carotid artery, and then a spiral preparation of the mesenteric artery was prepared so as not to remove the endothelium. Was produced. The sample at 37 ℃
A 0.5 g load was applied in Krebs-Henseleit solution to suspend it isometrically. For the continuous contraction caused by prostaglandin F ₂ α (3 × 10 ⁻⁶ M; Ono Yakuhin), the test compound was cumulatively added to calculate the 50% inhibitory concentration (IC ₅₀ value). The results are shown in Table 6.

[0035]

[Table 6] The compound of the present invention showed a superior prostaglandin F ₂ α antagonistic action as compared with the control drug.

Test Example 7 Improving effect of immunoglobulin E-involved asthma model Anti-benzylpenicilloyl bovine serum γ-globulin (BPO-BGG) in the femoral artery of a male Hartley guinea pig (about 400 g).
Sensitization was performed by administering 8 mg / kg. Approximately 48 hours later, those guinea pigs were anesthetized with urethane (1.5 g / kg, ip), and then the ventilation was measured with a sensor (Model 7020; Ugo basile) while ventilating with an artificial respirator (Model 683; Harvard). To K
It was performed according to the method of onzett-Rossler. The test compound was an antigen (benzylpenicilloyl bovine serum albumin (BPO-
BSA), 0.2 mg / kg, iv] Orally administered 2 hours before stimulation,
The effect was measured by considering the value after 3 minutes at which the reaction became maximum as 100% for complete occlusion, and calculated the 50% inhibition value (ED ₅₀ value). The results are shown in Table 7.

[0037]

[Table 7] The control drug did not show the improving effect on the immunoglobulin E-related asthma model, but the compound of the present invention showed the excellent improving effect on the immunoglobulin E-related asthma model.

Test Example 8 Acute Toxicity An acute toxicity test by intravenous administration was carried out using male ddY mice (5 weeks old). The LD ₅₀ value of the compound of Example 29 was 300 mg / kg or more, and high safety was confirmed.

[0039]

The present invention will be described below with reference to reference examples and examples, but the present invention is not limited to the specific details of these examples.

Reference Example 1 Methyl 4- (4-benzoylphenyl) butyrate 30.0 g Methyl 4-phenylbutyrate and benzoyl chloride 2
Under ice cooling, 44.9 g of anhydrous aluminum chloride was added little by little to a solution of 200 g of carbon disulfide in 3.7 g, and the mixture was heated under reflux for 4 hours. The reaction solution was cooled, poured into ice water, and extracted with methylene chloride. The methylene chloride layer was washed successively with water, an aqueous solution of potassium carbonate and water, dehydrated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 2: 1 → methylene chloride) to obtain 24.0 g of a light brown liquid. IR spectrum ν (liq) cm ^-1 : 1738, 1658 Mass spectrum m / z: 282 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.00 (2H, qn, J =
7.5Hz), 2.36 (2H, t, J = 7.5Hz), 2.74 (2H, t, J = 7.5Hz), 3.67
(3H, s), 7.29 (2H, d, J = 8.5Hz), 7.37-7.67 (3H, m), 7.78 (2H,
d, J = 8.5Hz), 7.70-7.87 (2H, m)

According to the method of Reference Example 1, the compounds of Reference Examples 2 to 9 were obtained.

Reference Example 2 Methyl 4- [4- (2-fluorobenzoyl) phenyl] butyrate Property Light tan liquid IR spectrum ν (liq) cm ^-1 : 1738, 1668 Mass spectrum m / z: 300 (M ⁺ ). NMR spectrum δ (CDCl ₃ ) ppm: 1.99 (2H, qn, J =
7.5Hz), 2.35 (2H, t, J = 7.5Hz), 2.73 (2H, t, J = 7.5Hz), 3.67
(3H, s), 7.16 (1H, t, J = 9Hz), 7.20-7.30 (3H, m), 7.45-7.60
(2H, m), 7.77 (2H, d, J = 7.5Hz)

Reference Example 3 Methyl 4- [4- (3-fluorobenzoyl) phenyl] butyrate Properties Light yellowish brown liquid IR spectrum ν (liq) cm ⁻¹ : 1738, 1662 Mass spectrum m / z: 300 (M ⁺ ). NMR spectrum δ (CDCl ₃ ) ppm: 2.00 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.75 (2H, t, J = 7.5Hz), 3.68
(3H, s), 7.20-7.33 (3H, m), 7.35-7.65 (3H, m), 7.74 (2H, d, J
= 8.5Hz)

Reference Example 4 Methyl 4- [4- (4-fluorobenzoyl) phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1738, 1660 Mass spectrum m / z: 300 (M ⁺ ) NMR Spectrum δ (CDCl ₃ ) ppm: 2.00 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.75 (2H, t, J = 7.5Hz), 3.68
(3H, s), 7.14 (1H, d, J = 8.5Hz), 7.17 (1H, d, J = 8.5Hz), 7.31
(2H, d, J = 8.5Hz), 7.71 (2H, d, J = 8.5Hz), 7.76-7.87 (2H, m)

Reference Example 5 Methyl 4- [4- (4-chlorobenzoyl) phenyl] butyrate Property Colorless scale-like crystals (i-Pr ₂ On-hexane) Melting point 64-65 ° C. Elemental analysis value C ₁₈ H ₁₇ ClO ₃ theory Value C _, 68.25; H, 5.41 Experimental value C _, 68.28; H, 5.46

Reference Example 6 Methyl 4- [4- (4-methylbenzoyl) phenyl] butyrate Properties Light yellowish brown liquid IR spectrum ν (liq) cm ⁻¹ : 1738, 1658 Mass spectrum m / z: 296 (M ⁺ ). NMR spectrum δ (CDCl ₃ ) ppm: 2.00 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.44 (3H, s), 2.74 (2H, t, J =
7.5Hz), 3.68 (3H, s), 7.27 (2H, d, J = 8.5Hz), 7.28 (2H, d, J =
8.5Hz), 7.71 (2H, d, J = 8.5Hz), 7.73 (2H, d, J = 8.5Hz)

Reference Example 7 Methyl 4- [4- (2-methoxybenzoyl) phenyl] butyrate Property Light yellowish brown liquid IR spectrum ν (liq) cm ^-1 : 1738, 1666 Mass spectrum m / z: 312 (M ⁺ ). NMR spectrum δ (CDCl ₃ ) ppm: 1.98 (2H, qn, J =
7.5Hz), 2.34 (2H, t, J = 7.5Hz), 2.71 (2H, t, J = 7.5Hz), 3.67
(3H, s), 3.74 (3H, s), 6.99 (1H, d, J = 8.5Hz), 7.03 (1H, t, J =
8.5Hz), 7.23 (2H, d, J = 8.5Hz), 7.27-7.60 (2H, m), 7.74 (2H,
(d, J = 8.5Hz)

Reference Example 8 Methyl 4- [4- (4-trifluoromethylbenzoyl) phenyl] butyrate Property Colorless plate crystal (n-hexane) Melting point 69.5-70.5 ° C. Elemental analysis value C ₁₉ H ₁₇ F ₃ O ₃ theoretical value C _, 65.14; H, 4.89 experimental value C _, 65.21; H, 4.86

Reference Example 9 Methyl 5- (4-benzoylphenyl) valerate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1738, 1660 Mass spectrum m / z: 296 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.60-1.79 (4H,
m), 2.26-2.42 (2H, m), 2.62-2.78 (2H, m), 3.67 (3H, s), 7.28
(2H, d, J = 8Hz), 7.47 (2H, t, J = 7.5Hz), 7.52-7.65 (1H, m), 7.
74 (2H, d, J = 8Hz), 7.80 (2H, dd, J = 7.5,1.5Hz)

Reference Example 10 Methyl 4- [4- (2-thenoyl) phenyl] butyrate Methyl 4-phenylbutyrate 5.00 g of carbon disulfide 25 ml
Under ice-cooling, 11.2 g of anhydrous aluminum chloride was added to the solution, 4.11 g of 2-thenoyl chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour and then heated under reflux for 3 hours. After cooling the reaction solution, the supernatant was removed by decanting, the insoluble residue was poured into ice water and extracted with methylene chloride. The methylene chloride layer was washed successively with aqueous potassium carbonate solution and water, dehydrated, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride → methylene chloride: ethyl acetate = 10:
Purification in 1) yielded 5.99 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 1738, 1634 Mass spectrum m / z: 288 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.01 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.75 (2H, t, J = 7.5Hz), 3.68
(3H, s), 7.16 (1H, dd, J = 4.5,3.5Hz), 7.31 (2H, d, J = 8.5Hz),
7.65 (1H, dd, J = 3.5,1Hz), 7.71 (1H, d, J = 4.5Hz)

Reference Example 11 Methyl 4- [4- (2-furoyl) phenyl] butyrate Methyl 4-phenylbutyrate 5.00 g of carbon disulfide 25 ml
Under ice cooling, 11.3 g of anhydrous aluminum chloride was added to the solution, 3.85 g of 2-furoyl chloride was added dropwise, and the mixture was heated under reflux for 3 hours. After cooling the reaction solution, the supernatant was removed by decanting, the insoluble residue was poured into ice water and extracted with methylene chloride. The methylene chloride layer was washed successively with aqueous potassium carbonate solution and water, dehydrated, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride → methylene chloride: ethyl acetate = 10: 1) to obtain 6.54 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 1738, 1646 Mass spectrum m / z: 272 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.01 (2H, qn, J =
7.5Hz), 2.36 (2H, t, J = 7.5Hz), 2.74 (2H, t, J = 7.5Hz), 3.68
(3H, s), 6.59 (1H, dd, J = 3,1.5Hz), 7.24 (1H, d, J = 3Hz), 7.31
(2H, d, J = 8Hz), 7.70 (1H, s), 7.93 (2H, d, J = 8Hz)

Reference Example 12 Methyl 4- [4- (hydroxyphenylmethyl) phenyl] butyrate Methyl 4- (4-benzoylphenyl) butyrate 14.0 g
1.88 g of sodium borohydride was added to 150 ml of a suspension of methanol in 150 ml under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed successively with diluted hydrochloric acid and water and dried.
The solvent was distilled off under reduced pressure to obtain 12.7 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3464, 1738 Mass spectrum m / z: 284 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.92 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.61 (2H, t, J = 7.5Hz), 3.63
(3H, s), 5.79 (1H, s), 7.13 (2H, d, J = 8Hz), 7.06-7.43 (7H, m)

According to the method of Reference Example 12, Reference Example 13
~ 22 compounds were obtained.

Reference Example 13 Methyl 4- (hydroxyphenylmethyl) phenylacetate Property Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 3432, 1736 Mass spectrum m / z: 256 (M ⁺ ) NMR spectrum δ (CDCl ₃ ). ppm: 3.60 (2H, s), 3.6
8 (3H, s), 5.83 (1H, s), 7.20-7.40 (9H, m)

Reference Example 14 Methyl 3- [4- (hydroxyphenylmethyl) phenyl] propionate Property Colorless liquid IR spectrum ν (liq) cm ^-1 : 3464, 1740 Mass spectrum m / z: 270 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.60 (2H, t, J = 8H
z), 2.92 (2H, t, J = 8Hz), 3.66 (3H, s), 5.81 (1H, s), 7.10-7.4
0 (9H, m)

Reference Example 15 Methyl 4- [4-[(2-fluorophenyl) hydroxymethyl] phenyl] butyrate Properties Light yellowish brown liquid IR spectrum ν (liq) cm ⁻¹ : 3464, 1738 Mass spectrum m / z: 302 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.62 (2H, t, J = 7.5Hz), 3.64
(3H, s), 6.11 (1H, s), 7.00 (1H, ddd, J = 10,8,1.5Hz), 7.05-
7.27 (4H, m), 7.31 (2H, d, J = 8Hz), 7.52 (1H, td, J = 8,2Hz)

Reference Example 16 Methyl 4- [4-[(3-fluorophenyl) hydroxymethyl] phenyl] butyrate Properties Light tan liquid IR spectrum ν (liq) cm ^-1 : 3464, 1738 Mass spectrum m / z: 302 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 2.10 (1H, br), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J =
7.5Hz), 3.65 (3H, s), 5.79 (1H, s), 6.80-7.35 (8H, m)

Reference Example 17 Methyl 4- [4-[(4-fluorophenyl) hydroxymethyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 3460, 1736 Mass spectrum m / z: 302 ( M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.92 (2H, qn, J =
7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.62 (2H, t, J = 7.5Hz), 3.64
(3H, s), 5.77 (1H, s), 7.00 (2H, t, J = 8.5Hz), 7.14 (2H, d, J = 8
Hz), 7.25 (2H, d, J = 8Hz), 7.32 (2H, dd, J = 8.5,5Hz)

Reference Example 18 Methyl 4- [4-[(4-chlorophenyl) hydroxymethyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 3464, 1736 Mass spectrum m / z: 318, 320 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.79 (1H, s), 7.15 (2H, d, J = 8Hz), 7.25 (2H, d, J = 8H
z), 7.30 (4H, s)

Reference Example 19 Methyl 4- [4- [hydroxy (4-methylphenyl) methyl] phenyl] butyrate Property Light yellowish brown liquid IR spectrum ν (liq) cm ^-1 : 3464, 1738 Mass spectrum m / z: 298 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.33 (3H, s), 2.62 (2H, t, J =
7.5Hz), 3.65 (3H, s), 5.79 (1H, s), 7.13 (4H, d, J = 8Hz), 7.25
(2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz)

Reference Example 20 Methyl 4- [4- [hydroxy (2-methoxyphenyl) methyl] phenyl] butyrate Property Light tan liquid IR spectrum ν (liq) cm ^-1 : 3496, 1736 Mass spectrum m / z: 314 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.65
(3H, s), 3.82 (3H, s), 6.89 (1H, d, J = 8.5Hz), 6.94 (1H, t, J =
8.5Hz), 7.13 (2H, d, J = 8Hz), 7.20-7.27 (2H, m), 7.30 (2H, d,
(J = 8Hz)

Reference Example 21 Methyl 4- [4- [hydroxy (4-trifluoromethylphenyl) methyl] phenyl] butyrate Property Colorless liquid IR spectrum ν (liq) cm ^-1 : 3464, 1738 Mass spectrum m / z: 352 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.86 (1H, s), 7.16 (2H, d, J = 8Hz), 7.27 (2H, d, J = 8H
z), 7.51 (2H, d, J = 8Hz), 7.30 (2H, d, J = 8Hz)

Reference Example 22 Methyl 5- [4- (hydroxyphenylmethyl) phenyl] valerate Property pale yellow liquid IR spectrum ν (liq) cm ^-1 : 3460, 1736 Mass spectrum m / z: 298 (M ⁺ ) NMR Spectrum δ (CDCl ₃ ) ppm: 1.49-1.75 (4H,
m), 2.10-2.39 (3H, m), 2.60 (2H, t, J = 7Hz), 3.65 (3H, s), 5.8
2 (1H, s), 7.14 (2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz), 7.20-7.4
3 (5H, m)

Reference Example 23 Methyl 4- [4- [hydroxy (2-thienyl) methyl] phenyl] butyrate Methyl 4- [4- (2-thenoyl) phenyl] butyrate 5.
To a solution of 57 g of methanol in 60 ml, 0.73 g of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and dehydrated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 4.12 g of a pale brown liquid. IR spectrum ν (liq) cm ^-1 : 3460, 1738 Mass spectrum m / z: 290 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.65 (2H, t, J = 7.5Hz), 3.66
(3H, s), 6.03 (1H, s), 6.88 (1H, d, J = 3.5Hz), 6.94 (1H, dd, J =
5,3.5Hz), 7.18 (2H, d, J = 8Hz), 7.25 (1H, d, J = 5Hz), 7.36 (2
(H, d, J = 8Hz)

Reference Example 24 Methyl 4- [4-[(2-furyl) hydroxymethyl] phenyl] butyrate Methyl 4- [4- (2-Furoyl) phenyl] butyrate 6.
To a solution of 44 g of methanol in 60 ml, 0.89 g of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and dehydrated, and the solvent was distilled off under reduced pressure to obtain 5.91 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 3460, 1736 Mass spectrum m / z: 274 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.96 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.80 (1H, s), 6.13 (1H, d, J = 3Hz), 6.32 (1H, dd, J = 3,
2Hz), 7.18 (2H, d, J = 8Hz), 7.35 (2H, d, J = 8Hz), 7.39 (1H, d, J
= 2Hz)

Reference Example 25 Methyl 4- [4- (chlorophenylmethyl) phenyl] butyrate 4.04 ml of thionyl chloride was added to a solution of 12.4 g of methyl 4- [4- (hydroxyphenylmethyl) phenyl] butyrate in 40 ml of benzene. The mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, ether was added to the residue, and the mixture was washed with water. After drying the ether layer, the solvent was distilled off under reduced pressure to obtain 12.5 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 302, 304 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.65
(3H, s), 6.11 (1H, s), 7.15 (2H, d, J = 8.5Hz), 7.20-7.46 (7H,
m)

According to the method of Reference Example 25, Reference Example 26
~ 35 compounds were obtained.

Reference Example 26 Methyl 4- (chlorophenylmethyl) phenylacetate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 274, 276 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 3.62 (2H, s), 3.6
9 (3H, s), 6.11 (1H, s), 7.20-7.45 (9H, m)

Reference Example 27 Methyl 3- [4- (chlorophenylmethyl) phenyl] propionate Property Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 1738 Mass spectrum m / z: 288, 290 (M ⁺ , 3: 1) ) NMR spectrum δ (CDCl ₃ ) ppm: 2.62 (3H, t, J = 7.
5Hz), 2.94 (3H, t, J = 7.5Hz), 3.67 (3H, s), 6.11 (1H, s), 7.15
-7.45 (9H, m)

Reference Example 28 4- [4- [chloro (2-fluorophenyl) methyl]
Phenyl] methyl butyrate Properties Light yellowish brown liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 320, 322 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.65
(3H, s), 6.42 (1H, s), 6.95-7.07 (1H, m), 7.10-7.17 (3H, m),
7.20-7.40 (3H, m), 7.56 (1H, td, J = 8,1.5Hz)

Reference Example 29 4- [4- [chloro (3-fluorophenyl) methyl]
Phenyl] methyl butyrate Properties Light yellowish brown liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 320, 322 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.65 (2H, t, J = 7.5Hz), 3.66
(3H, s), 6.07 (1H, s), 6.90-7.07 (1H, m), 7.06-7.40 (7H, m)

Reference Example 30 4- [4- [chloro (4-fluorophenyl) methyl]
Phenyl] methyl butyrate Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 320, 322 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn , J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.66
(3H, s), 6.10 (1H, s), 7.03 (2H, t, J = 9Hz), 7.16 (2H, d, J = 8H
z), 7.30 (2H, d, J = 8Hz), 7.38 (2H, dd, J = 9,5Hz)

Reference Example 31 Methyl 4- [4- [4- (chloro (4-chlorophenyl) methyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1740 Mass spectrum m / z 336, 338, 340 (M ⁺ , 9: 6:
1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.66
(3H, s), 6.07 (1H, s), 7.16 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8H
z), 7.33 (4H, s)

Reference Example 32 Methyl 4- [4- [chloro (4-methylphenyl) methyl] phenyl] butyrate Properties Light yellow-green liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z 316, 318 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.33 (3H, s), 2.63 (2H, t, J =
7.5Hz), 3.65 (3H, s), 6.09 (1H, s), 7.14 (4H, d, J = 8Hz), 7.29
(2H, d, J = 8Hz), 7.32 (2H, d, J = 8Hz)

Reference Example 33 4- [4- [chloro (2-methoxyphenyl) methyl]
Phenyl] methyl butyrate Properties Light brown liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 332, 334 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn , J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.65
(3H, s), 3.83 (3H, s), 6.58 (1H, s), 6.87 (1H, d, J = 8Hz), 6.97
(1H, d, J = 8Hz), 7.13 (2H, d, J = 8.5Hz), 7.20-7.30 (1H, m), 7.
34 (2H, d, J = 8.5Hz), 7.51 (1H, dd, J = 8,1.5Hz)

Reference Example 34 Methyl 4- [4- [chloro (4-trifluoromethylphenyl) methyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z 370, 372 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.65 (2H, t, J = 7.5Hz), 3.66
(3H, s), 6.12 (1H, s), 7.17 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8H
z), 7.54 (2H, d, J = 8Hz), 7.61 (2H, d, J = 8Hz)

Reference Example 35 Methyl 5- [4- (chlorophenylmethyl) phenyl] valerate Property pale yellow liquid IR spectrum ν (liq) cm ⁻¹ : 1738 NMR spectrum δ (CDCl ₃ ) ppm: 1.57-1.75 (4H,
m), 2.33 (2H, t, J = 7Hz), 2.61 (2H, t, J = 7Hz), 3.66 (3H, s), 6.
11 (1H, s), 7.14 (2H, d, J = 8Hz), 7.31 (2H, d, J = 8Hz), 7.20-7.
48 (5H, m)

Reference Example 36 Methyl 4- [4- [chloro (2-thienyl) methyl] phenyl] butyrate Into a 50 ml benzene solution of 5.84 g of methyl 4- [4- [hydroxy [2-thienyl] methyl] phenyl] butyrate. ,
1.90 ml of thionyl chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 6.20 g of a pale brown liquid. IR spectrum ν (liq) cm ^-1 : 1736 Mass spectrum m / z: 308, 310 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.96 (2H, qn, J =
7.5Hz), 2.34 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 3.66
(3H, s), 6.30 (1H, s), 6.90-6.95 (2H, m), 7.19 (2H, d, J = 8.5H
z), 7.29 (1H, d, J = 5,1Hz), 7.42 (2H, d, J = 8.5Hz)

Reference Example 37 Methyl 4- [4- (azidophenylmethyl) phenyl] butyrate 12.0 g of methyl 4- [4- (chlorophenylmethyl) phenyl] butyrate and 5.20 g of sodium azide in N, N
A 60 ml suspension of dimethylformamide was heated at 50-60 ° C. for 4 hours. After cooling the reaction mixture, water was added and the mixture was extracted with ether. The ether layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-
Purification with hexane: methylene chloride = 1: 1) gave 10.8 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 309 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.68 (1H, s), 7.10-7.39 (9H, m)

According to the method of Reference Example 37, Reference Example 38
~ 47 compounds were obtained.

Reference Example 38 Methyl 4- (azidophenylmethyl) phenylacetate Property Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 2104, 1740 Mass spectrum m / z: 281 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 3.61 (2H, s), 3.6
9 (3H, s), 5.69 (1H, s), 7.25-7.36 (9H, m)

Reference Example 39 Methyl 3- [4- (azidophenylmethyl) phenyl] propionate Property Colorless liquid IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 295 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.62 (2H, t, J = 8H
z), 2.94 (2H, t, J = 8Hz), 3.13 (3H, s), 5.68 (1H, s), 7.16-7.3
9 (5H, m)

Reference Example 40 4- [4- [azido (2-fluorophenyl) methyl]]
Phenyl] methyl butyrate Properties Light yellowish brown liquid IR spectrum ν (liq) cm ^-1 : 2108, 1738 Mass spectrum m / z: 327 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.65
(3H, s), 6.02 (1H, s), 6.80-7.45 (8H, m)

Reference Example 41 4- [4- [azido (3-fluorophenyl) methyl]]
Phenyl] methyl butyrate Properties Light brown liquid IR spectrum ν (liq) cm ^-1 : 2108, 1736 Mass spectrum m / z: 327 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.65 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.66 (1H, s), 6.90-7.40 (8H, m)

Reference Example 42 4- [4- [azido (4-fluorophenyl) methyl]]
Phenyl] methyl butyrate Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 327 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.67 (1H, s), 7.04 (2H, t, J = 9Hz), 7.18 (4H, s), 7.28
(2H, dd, J = 9,5Hz)

Reference Example 43 Methyl 4- [4- [azido (4-chlorophenyl) methyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 343, 345 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.65 (1H, s), 7.18 (4H, s), 7.24 (2H, d, J = 9Hz), 7.33
(2H, d, J = 9Hz)

Reference Example 44 Methyl 4- [4- [azido (4-methylphenyl) methyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ⁻¹ : 2104, 1738 Mass spectrum m / z: 323 ( M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.34 (3H, s), 2.63 (2H, t, J =
7.5Hz), 3.66 (3H, s), 5.65 (1H, s), 7.05-7.30 (8H, m)

Reference Example 45 4- [4- [azido (2-methoxyphenyl) methyl]]
Phenyl] methyl butyrate Properties Light brown liquid IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 339 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.65
(3H, s), 3.82 (3H, s), 6.14 (1H, s), 6.89 (1H, d, J = 8Hz), 6.93
(1H, t, J = 8.5Hz), 7.14 (2H, d, J = 8.5Hz), 7.20-7.30 (4H, m)

Reference Example 46 Methyl 4- [4- [azido (4-trifluoromethylphenyl) methyl] phenyl] butyrate Property Colorless liquid IR spectrum ν (liq) cm ^-1 : 2108, 1738 Mass spectrum m / z: 377 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.65 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.73 (1H, s), 7.19 (4H, s), 7.44 (2H, d, J = 8Hz), 7.61
(2H, d, J = 8Hz)

Reference Example 47 Methyl 5- [4- (azidophenylmethyl) phenyl] valerate Property Yellow liquid IR spectrum ν (liq) cm ⁻¹ : 2104, 1738 NMR spectrum δ (CDCl ₃ ) ppm: 1.58-1.75 ( 4H,
m), 2.33 (2H, t, J = 7Hz), 2.61 (2H, t, J = 7Hz), 3.66 (3H, s), 5.
68 (1H, s), 7.15 (2H, d, J = 8.5Hz), 7.21 (2H, d, J = 8.5Hz), 7.2
3-7.41 (5H, m)

Reference Example 48 Methyl 4- [4- [azido (2-thienyl) methyl] phenyl] butyrate 6.10 g of methyl 4- [4- [chloro [2-thienyl) methyl] phenyl] butyrate and sodium azide 2 .57
g of N, N-dimethylformamide in 50 ml of suspension was added to 4
The mixture was heated and stirred at 0 ° C for 2 hours. After cooling, water was added to the reaction solution and extracted with ether. The ether layer was washed with water and dehydrated, and then the solvent was distilled off under reduced pressure to obtain 5.58 g of a pale brown liquid. IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 315 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.96 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.87 (1H, s), 6.94 (1H, d, J = 3.5Hz), 6.97 (1H, dd, J =
5,3.5Hz), 7.20 (2H, d, J = 8Hz), 7.29 (1H, d, J = 5,1.5Hz), 7.3
1 (2H, d, J = 8Hz)

Reference Example 49 4- [4- [azido (2-furyl) methyl] phenyl]
Methyl butyrate 4- [4- [2-furyl) hydroxymethyl] phenyl] methyl butyrate 3.48 g and triethylamine 1.9
5 ml of anhydrous N, N-dimethylformamide solution was charged with methanesulfonyl chloride 1.45 at an internal temperature of -20 to -15 ° C.
g was added dropwise, and the mixture was stirred at an internal temperature of -15 to 0 ° C for 20 minutes. 2.06 g of sodium azide was added to the reaction solution at an internal temperature of 0 ° C., the mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ether. The ether layer was washed with water and dehydrated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 5: 1) to obtain 1.59 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 299 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.96 (2H, qn, J =
7.5Hz), 2.33 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.62 (1H, s), 6.20 (1H, d, J = 3Hz), 6.34 (1H, dd, J = 3,
2Hz), 7.20 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8Hz), 7.42 (1H, d, J
= 2Hz)

Reference Example 50 4- [4- (Azidophenylmethyl) phenyl] butyric acid Methyl 4- [4- (azidophenylmethyl) phenyl] butyrate 0.50 g was added to a solution of 0.50 g of methanol in 2.0 ml of 2N sodium hydroxide. Was added and stirred at room temperature for 4.5 hours. The reaction solvent was evaporated under reduced pressure, water was added to the residue, the mixture was acidified with diluted hydrochloric acid, and then extracted with methylene chloride. The methylene chloride layer was washed with water and dehydrated, then the solvent was distilled off under reduced pressure to give a pale yellow liquid (0.1%).
46 g was obtained. IR spectrum ν (liq) cm ^-1 : 2104, 1706 Mass spectrum m / z: 295 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 5.68
(1H, s), 7.17 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz), 7.26-7.37
(5H, m)

Reference Example 51 (+)-4- [4- (azidophenylmethyl) phenyl] butyric acid 4- [4- (azidophenylmethyl) phenyl] butyric acid 6
5.9 g and L-(-)-1-phenylethylamine 2
Crystals precipitated from a solution of 7.9 g of ethyl acetate in 150 ml were recrystallized 6 times from ethyl acetate to give a melting point of 118-12.
13.7 g of colorless needle crystals at 1 ° C. were obtained. Elemental analysis C ₁₇ H ₁₇ N ₃ O ₂ · C ₈ H ₁₁ N Theoretical value C _, 72.09; H, 6.78; N, 13.45 Experimental value C _, 72.21; H, 6.82; N, 13.42 Specific optical rotation [α] _D ²⁰ + 15.8 ° (c = 1, MeOH) 13.0 g of this product was added to a hydrochloric acid aqueous solution to give a free acid, which was extracted with ether. After washing the ether layer with water and dehydration,
The solvent was distilled off to obtain 8.70 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 2104, 1710 Mass spectrum m / z: 295 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 5.68
(1H, s), 7.17 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz), 7.28-7.37
(5H, m) Specific rotation [α] _D ²⁰ + 19.3 ° (c = 1, MeOH)

Reference Example 52 (-)-4- [4- (azidophenylmethyl) phenyl] butyric acid 4- [4- (azidophenylmethyl) phenyl] butyric acid and L-(-)-1-phenyl of Reference Example 66 36.8 g of 4- [4- (azidophenylmethyl) phenyl] butyric acid and D- recovered from the mother liquor after salt formation with ethylamine
Crystals extracted from a solution of 15.1 g of (+)-1-phenylethylamine in 120 ml of ethyl acetate were recrystallized 6 times from ethyl acetate to give colorless needles having a melting point of 117 to 120 ° C.
1.1 g was obtained. Elemental analysis value C ₁₇ H ₁₇ N ₃ O ₂ · C ₈ H ₁₁ N theoretical value C _, 72.09; H, 6.78; N, 13.45 experimental value C _, 72.19; H, 6.80; N, 13.46 Specific optical rotation [α] _D ²⁰ - and 15.3 ° (c = 1, MeOH ) the free acid was added to this product 10.5g in hydrochloric acid solution and extracted with ether. After washing the ether layer with water and dehydration,
The solvent was distilled off to obtain 7.17 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 2104, 1710 Mass spectrum m / z: 295 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz), 5.68
(1H, s), 7.17 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz), 7.28-7.38
(5H, m) Specific rotation [α] ^{_{D 20 - 19.2 ° (c =}} 1, MeOH)

Reference Example 53 Methyl (-)-4- [4- (azidophenylmethyl) phenyl] butyrate (-)-4- [4- (Azidophenylmethyl) phenyl] butyric acid 6.84 g and potassium carbonate 3.53 g N of
2.0 ml of methyl iodide was added to a 40 ml suspension of N-dimethylformamide, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ether. Wash the ether layer with water,
After dehydration, the solvent was distilled off under reduced pressure to obtain 6.77 g of a light brown liquid. IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 309 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.68 (1H, s), 7.16 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8H
z), 7.27-7.38 (5H, m ) Specific rotation [α] ^{_{D 20 - 19.4 ° (c =}} 1, MeOH)

Reference Example 54 Methyl (+)-4- [4- (azidophenylmethyl) phenyl] butyrate In accordance with Reference Example 53, (+)-4- [4- (azidophenylmethyl) phenyl] butyric acid 5. From 29 g, 5.14 g of colorless liquid was obtained. IR spectrum ν (liq) cm ^-1 : 2104, 1738 Mass spectrum m / z: 309 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.68 (1H, s), 7.16 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8H
z), 7.28-7.37 (7H, m) Specific rotation [α] _D ²⁰ + 19.6 ° (c = 1, MeOH)

Reference Example 55 Methyl 4- [4- (aminophenylmethyl) phenyl] butyrate Methyl 4- [4- (azidophenylmethyl) phenyl] butyrate 7.00 g of methanol was dissolved in 70 ml of methanol and platinum oxide 1 was added.
80 mg was added and hydrogenation was carried out at normal temperature and normal pressure for 5 hours. After removing the catalyst by filtration, the filtrate was evaporated under reduced pressure to obtain 6.20 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3384, 1736 Mass spectrum m / z: 283 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.32 (2H, br-s), 2.61 (2H, t,
J = 7.5Hz), 3.64 (3H, s), 5.19 (1H, s), 7.06-7.46 (7H, m), 7.1
1 (2H, d, J = 8.5Hz)

According to the method of Reference Example 55, Reference Example 56
~ 65 compounds were obtained.

Reference Example 56 Methyl 4- (aminophenylmethyl) phenylacetate Property Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 3380, 1736 Mass spectrum m / z: 255 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.59 (2H, br), 3.
59 (2H, s), 3.67 (3H, s), 5.22 (1H, s), 7.11-7.42 (9H, m)

Reference Example 57 Methyl 3- [4- (aminophenylmethyl) phenyl] propionate Property Colorless liquid IR spectrum ν (liq) cm ^-1 : 3380, 1738 Mass spectrum m / z: 269 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, br-s),
2.59 (2H, t, J = 8Hz), 2.91 (2H, t, J = 8Hz), 3.65 (3H, s), 5.17
(1H, s), 7.10-7.38 (9H, m)

Reference Example 58 4- [4- [amino (2-fluorophenyl) methyl]]
Phenyl] methyl butyrate Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 3384, 3320, 1
738 Mass spectrum m / z: 301 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.90 (2H, s), 1.9
3 (2H, qn, J = 7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.62 (2H, t, J = 7.
5Hz), 3.65 (3H, s), 5.48 (1H, s), 6.99 (1H, ddd, J = 10.5,8,1.
5Hz), 7.08-7.28 (2H, m), 7.12 (2H, d, J = 8Hz), 7.31 (2H, d, J =
8Hz), 7.45 (1H, td, J = 8,2Hz)

Reference Example 59 4- [4- [Amino (3-fluorophenyl) methyl]]
Phenyl] methyl butyrate Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 3384, 3316, 1
738 Mass spectrum m / z: 301 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.86 (2H, s), 1.9
3 (2H, quin, J = 7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.62 (2H, t, J =
7.5Hz), 3.65 (3H, s), 5.17 (1H, s), 6.83-6.97 (1H, m), 7.02-
7.30 (3H, m), 7.12 (2H, d, J = 8.5Hz), 7.26 (2H, d, J = 8.5Hz)

Reference Example 60 4- [4- [amino (4-fluorophenyl) methyl]
Phenyl] methyl butyrate Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 3384, 3316, 1
736 Mass spectrum m / z: 301 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.83-2.01 (4H,
m), 2.32 (2H, t, J = 7.5Hz), 2.62 (2H, t, J = 7.5Hz), 3.65 (3H,
s), 5.17 (1H, s), 6.98 (2H, t, J = 8.5Hz), 7.12 (2H, d, J = 8.5H
z), 7.26 (2H, d, J = 8.5Hz), 7.34 (2H, dd, J = 8.5,5.5Hz)

Reference Example 61 Methyl 4- [4- [amino (4-chlorophenyl) methyl] phenyl] butyrate Property Light brown liquid IR spectrum ν (liq) cm ^-1 : 3384, 3316, 1
738 Mass spectrum m / z: 317, 319 (M ⁺ , 3: 1) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J = 8
Hz), 2.32 (2H, t, J = 8Hz), 2.62 (2H, t, J = 8Hz), 3.65 (3H, s),
5.18 (1H, s), 7.12 (2H, d, J = 8.5Hz), 7.25 (2H, d, J = 8.5Hz),
7.27 (2H, d, J = 8.5Hz), 7.32 (2H, d, J = 8.5Hz)

Reference Example 62 Methyl 4- [4- [amino (4-methylphenyl) methyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ^-1 : 3384, 3320, 1
738 Mass spectrum m / z: 297 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.88 (2H, s), 1.9
2 (2H, qn, J = 7.5Hz), 2.31 (3H, s), 2.31 (2H, t, J = 7.5Hz), 2.6
1 (2H, t, J = 7.5Hz), 3.65 (3H, s), 5.15 (1H, s), 7.11 (2H, d, J =
8Hz), 7.11 (2H, d, J = 6.5Hz), 7.25 (2H, d, J = 8Hz), 7.28 (2H,
(d, J = 6.5Hz)

Reference Example 63 4- [4- [amino (2-methoxyphenyl) methyl]
Phenyl] methyl butyrate Properties colorless liquid IR spectrum ν (liq) cm ^-1 : 3384, 3316, 1
738 Mass spectrum m / z: 313 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 1.96-2.22 (2H, br), 2.32 (2H, t, J = 7.5Hz), 2.62 (2
H, t, J = 7.5Hz), 3.65 (3H, s), 3.79 (3H, s), 5.48 (1H, s), 6.85
(1H, d, J = 8Hz), 6.91 (1H, td, J = 7.5,1Hz), 7.10 (2H, d, J = 8H
z), 7.21 (1H, td, J = 7.5,1Hz), 7.26 (1H, dd, J = 7.5,1Hz), 7.3
0 (2H, d, J = 8Hz)

Reference Example 64 Methyl 4- [4- [amino (4-trifluoromethylphenyl) methyl] phenyl] butyrate Property Light brown liquid IR spectrum ν (liq) cm ^-1 : 3388, 3320, 1
738 Mass spectrum m / z: 351 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.93 (2H, qn, J =
7.5Hz), 1.80-2.20 (2H, br), 2.32 (2H, t, J = 7.5Hz), 2.62 (2
H, t, J = 7.5Hz), 3.65 (3H, s), 5.24 (1H, s), 7.13 (2H, d, J = 8.5
Hz), 7.26 (2H, d, J = 8.5Hz), 7.51 (2H, d, J = 8.5Hz), 7.56 (2H,
(d, J = 8.5Hz)

Reference Example 65 Methyl 5- [4- (aminophenylmethyl) phenyl] valerate Properties pale yellow liquid IR spectrum ν (liq) cm ^-1 : 3384, 3316, 1
738 Mass spectrum m / z: 297 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.51-1.75 (4H,
m), 1.90 (2H, s), 2.32 (2H, t, J = 7Hz), 2.59 (2H, t, J = 7Hz), 3.
65 (3H, s), 5.18 (1H, s), 7.11 (2H, d, J = 8.5Hz), 7.27 (2H, d, J
= 8.5Hz), 7.17-7.41 (5H, m)

Reference Example 66 Methyl (+)-4- [4- (aminophenylmethyl) phenyl] butyrate Methyl (-)-4- [4- (azidophenylmethyl) phenyl] butyrate 6.70 g of methanol in a solution of 70 ml of methanol. ,
110 mg of platinum oxide was added, and hydrogenation was carried out at room temperature and normal pressure for 3.5 hours. After removing the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ether and acidified with dilute hydrochloric acid. The precipitated crystals were collected by filtration to obtain 5.80 g of colorless crystals of hydrochloride. Recrystallization from water gave colorless needle crystals with a melting point of 209-213 ° C. Elemental analysis C ₁₈ H ₂₁ NO ₂ · HCl theory _{C, 67.60; H, 6.93;} N, 4.38 Found _{C, 67.59; H, 6.91;} N, 4.42 Specific rotation [α] _D ²⁰ - 1.1 ° (c = 1, MeOH) 5.30 g of hydrochloride was dissolved in water, made alkaline with potassium carbonate, and extracted with ether. The ether layer is washed with water,
After dehydration, the solvent was distilled off under reduced pressure to obtain 4.58 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3384, 3312, 1
738 Mass spectrum m / z: 283 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.68 (2H, brs),
1.93 (2H, qn, J = 7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.61 (2H, t, J
= 7.5Hz), 3.65 (3H, s), 5.18 (1H, s), 7.12 (2H, d, J = 8Hz), 7.1
9-7.39 (7H, m) Specific optical rotation (α) _D ²⁰ + 1.1 ° (c = 1, MeOH)

REFERENCE EXAMPLE 67 Methyl (-)-4- [4- (aminophenylmethyl) phenyl] butyrate Methyl (+)-4- [4- (azidophenylmethyl) phenyl] methyl butyrate 4.79 g of methanol in 50 ml of methanol. ,
96 mg of platinum oxide was added, and hydrogenation was carried out at normal temperature and normal pressure for 2 hours. After removing the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ether and acidified with dilute hydrochloric acid. The precipitated crystals were collected by filtration to give 4.44 g of colorless hydrochloride crystals. Recrystallization from water gave colorless needles with a melting point of 208-212 ° C. Elemental analysis value C ₁₈ H ₂₁ NO ₂ · HCl theoretical value C _, 67.60; H, 6.93; N, 4.38 experimental value C _, 67.59; H, 6.91; N, 4.36 specific rotation [α] _D ²⁰ + 1.2 ° (c = 1, MeOH) 3.94 g of hydrochloride was dissolved in water, made alkaline with potassium carbonate, and extracted with ether. Wash the ether layer with water,
After dehydration, the solvent was distilled off under reduced pressure to obtain 3.45 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3384, 3312, 1
738 Mass spectrum m / z: 283 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.71 (2H, brs),
1.93 (2H, qn, J = 7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.61 (2H, t, J
= 7.5Hz), 3.65 (3H, s), 5.18 (1H, s), 7.12 (2H, d, J = 8Hz), 7.2
0-7.38 (7H, m) Specific rotation [α] ^{_{D 20 - 1.3 ° (c =}} 1, MeOH)

Reference Example 68 Methyl 4- [4- [amino (2-thienyl) methyl] phenyl] butyrate Methyl 4- [4- [4- [azido (2-thienyl) methyl] phenyl] butyrate 4.00 g of methanol in 40 ml of methanol. ,
40 mg of platinum oxide was added, and hydrogenation was carried out at normal temperature and normal pressure for 6 hours. After removing the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in dilute hydrochloric acid and washed with ether. Potassium carbonate was added to the aqueous layer to make it alkaline, and the mixture was extracted with ether. The ether layer was washed with water and dehydrated, and then the solvent was distilled off under reduced pressure to obtain 3.04 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 3384, 3312, 1
736 Mass spectrum m / z: 289 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.94 (2H, qn, J =
7.5Hz), 2.02 (2H, brs), 2.32 (2H, t, J = 7.5Hz), 2.63 (2H, t, J
= 7.5Hz), 3.66 (3H, s), 5.39 (1H, s), 6.83 (1H, d, J = 3.5Hz),
6.91 (1H, dd, J = 5,3.5Hz), 7.15 (2H, d, J = 8Hz), 7.19 (1H, dd,
J = 5,1Hz), 7.33 (2H, d, J = 8Hz)

Reference Example 69 4- [4- [amino (2-furyl) methyl] phenyl]
Methyl butyrate 4- [4- [azido (2-furyl) methyl] phenyl]
20 mg of platinum oxide was added to a solution of 1.56 g of methyl butyrate in 20 ml of methanol, and hydrogenation was carried out at room temperature and normal pressure for 4.5 hours. After removing the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in dilute hydrochloric acid and washed with ether. Potassium carbonate was added to the aqueous layer to make it alkaline, and the mixture was extracted with ether. The ether layer was washed with water and dehydrated, and then the solvent was distilled off under reduced pressure to obtain 0.90 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 3376, 3304, 1
738 Mass spectrum m / z: 273 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.95 (2H, qn, J =
7.5Hz), 2.00-2.38 (2H, br), 2.33 (2H, t, J = 7.5Hz), 2.64 (2
H, t, J = 7.5Hz), 3.66 (3H, s), 5.14 (1H, s), 6.10 (1H, d, J = 3H
z), 6.30 (1H, dd, J = 3,2Hz), 7.16 (2H, d, J = 8Hz), 7.29 (2H, d,
J = 8Hz), 7.34 (1H, s)

Example 1 Methyl 4- [4- [phenyl (phenylsulfonylamino) methyl] phenyl] butyrate Methyl 4- [4- (aminophenylmethyl) phenyl] butyrate 2.50 g and triethylamine 1.35 ml methylene chloride 10 ml A solution of benzenesulfonyl chloride (1.56 g) in methylene chloride (5 ml) was added to the solution under ice cooling. The reaction solution was stirred at room temperature for 30 minutes and then washed successively with diluted hydrochloric acid and water. After drying the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 2.70 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3288, 1736, 1
328 NMR spectrum δ (CDCl ₃ ) ppm: 1.88 (2H, qn, J =
7.5Hz), 2.28 (2H, t, J = 7.5Hz), 2.56 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.32 (1H, d, J = 7.5Hz), 5.58 (1H, d, J = 7.5Hz), 7.06-
7.52 (12H, m), 7.66 (2H, dd, J = 8.5,1.5Hz)

In accordance with the method of Example 1, Examples 2 to 4
Was obtained.

Example 2 4- [phenyl (phenylsulfonylamino) methyl]
Methyl phenylacetate Property Colorless liquid IR spectrum ν (liq) cm ^-1 : 3288, 1736, 1
328 NMR spectrum δ (CDCl ₃ ) ppm: 3.55 (2H, s), 3.6
8 (3H, s), 5.15 (1H, d, J = 7Hz), 5.58 (1H, d, J = 7Hz), 7.04-7.5
0 (12H, m), 7.67 (2H, dd, J = 7,1.5Hz)

Example 3 Methyl 3- [4- [phenyl (phenylsulfonylamino) methyl] phenyl] propionate Property colorless needle crystals (EtOH) Melting point 132-134 ° C. Elemental analysis value C ₂₃ H ₂₃ NO ₄ S theoretical value C _, 67.46; H, 5.66; N, 3.42 Experimental value C _, 67.54; H, 5.79; N, 3.34

Example 4 Methyl 4- [4-[(4-fluorophenyl) (phenylsulfonylamino) methyl] phenyl] butyrate Property Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 3280, 1736 NMR spectrum δ (CDCl ₃ ) ppm: 1.89 (2H, qn, J =
7.5Hz), 2.29 (2H, t, J = 7.5Hz), 2.57 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.13 (1H, d, J = 7Hz), 5.56 (1H, d, J = 7Hz), 6.89 (2H,
t, J = 8.5Hz), 6.95 (2H, d, J = 8Hz), 7.02 (2H, d, J = 8Hz), 7.08
(2H, dd, J = 8.5,5Hz), 7.34 (2H, t, J = 8Hz), 7.48 (1H, t, J = 7.5
Hz), 7.66 (2H, dd, J = 8,1Hz)

Example 5 4- [4-[(4-chlorophenylsulfonylamino)
Methyl phenylmethyl] phenyl] butyrate Methyl 4- [4-[(amino) phenylmethyl] phenyl] butyrate 2.50 g and triethylamine 1.35 ml in a solution of methylene chloride 10 ml under ice cooling, 4-chlorobenzenesulfonyl chloride 1.86 g. 5 ml of methylene chloride solution was added. After stirring the reaction solution at room temperature for 30 minutes, diluted hydrochloric acid,
It was washed successively with water. After drying the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 3.00 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3284, 1736, 133
6 NMR spectrum δ (CDCl ₃ ) ppm: 1.90 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.58 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.24 (1H, d, J = 7.5Hz), 5.59 (1H, d, J = 7.5Hz), 6.92-
7.30 (11H, m), 7.54 (2H, d, J = 8.5Hz)

In accordance with the method of Example 5, Examples 6 to 1
5 compound was obtained.

Example 6 Methyl 4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenylacetate Properties colorless liquid IR spectrum ν (liq) cm ^-1 : 3280, 1736, 1
334 NMR spectrum δ (CDCl ₃ ) ppm: 3.57 (2H, s), 3.6
9 (3H, s), 5.24 (1H, d, J = 7Hz), 5.60 (1H, d, J = 7Hz), 7.01-7.2
9 (11H, m), 7.54 (2H, d, J = 8.5Hz)

Example 7 3- [4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenyl] methyl propionate Properties colorless liquid IR spectrum ν (liq) cm ^-1 : 3284, 1738, 1
332 NMR spectrum δ (CDCl ₃ ) ppm: 2.57 (2H, t, J = 8H
z), 2.88 (2H, t, J = 8Hz), 3.66 (3H, s), 5.36 (1H, d, J = 7.5Hz),
5.58 (1H, d, J = 7.5Hz), 6.99-7.27 (11H, m), 7.54 (2H, d, J = 9H
z)

Example 8 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (2-fluorophenyl) methyl] phenyl] butyrate Properties Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 3284, 1738 NMR spectrum δ (CDCl ₃ ) ppm: 1.90 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.59 (2H, t, J = 7.5Hz), 3.65
(3H, s), 5.31 (2H, d, J = 7.5Hz), 5.77 (2H, d, J = 7.5Hz), 6.89
(1H, dd, J = 10.5,8.5Hz), 6.95-7.25 (3H, m), 7.06 (4H, s), 7.
26 (2H, d, J = 8.5Hz), 7.59 (2H, d, J = 8.5Hz)

Example 9 4- [4-[(4-chlorophenylsulfonylamino)
(3-Fluorophenyl) methyl] phenyl] methyl methyl butyrate Properties Colorless columnar crystals (EtOH) Melting point 87-88 ° C Elemental analysis C ₂₄ H ₂₃ ClFNO ₄ S Theoretical C _, 60.56; H, 4.87; N, 2.94 Experimental C _, 60.47; H, 4.86; N, 2.89

Example 10 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (4-fluorophenyl) methyl] phenyl] butyrate Properties Colorless plate crystal (i-Pr ₂ O-MeOH) Melting point 89.5-91 ° C Elemental analysis value C ₂₄ H ₂₃ ClFNO ₄ S Theoretical value C _, 60.56; H , 4.87; N, 2.94 Experimental value C _, 60.47; H, 5.01; N, 2.77

Example 11 Methyl 4- [4-[(4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl] phenyl] butyrate Property Light yellow liquid IR spectrum ν (liq) cm ⁻¹ : 3280, 1738 NMR spectrum δ (CDCl ₃ ) ppm: 1.90 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.59 (2H, t, J = 7.5Hz), 3.67
(3H, s), 5.09 (1H, d, J = 7.5Hz), 5.55 (1H, d, J = 7.5Hz), 6.94
(2H, d, J = 8.5Hz), 7.03 (2H, d, J = 8.5Hz), 7.07 (2H, d, J = 8.5H
z), 7.21 (2H, d, J = 8.5Hz), 7.30 (2H, d, J = 8.5Hz), 7.56 (2H,
(d, J = 8.5Hz)

Example 12 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (4-methylphenyl) methyl] phenyl] butyrate Properties Colorless needle crystals (i-Pr ₂ O-EtOH) Melting point 89.5-90.5 ° C Elemental analysis value C ₂₅ H ₂₆ ClNO ₄ S Theoretical value C _, 63.62 H, 5.55; N, 2.97 experimental value C _, 63.61; H, 5.57; N, 2.97

Example 13 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (2-methoxyphenyl) methyl] phenyl] butyrate Properties Colorless liquid IR spectrum ν (liq) cm ⁻¹ : 3292, 1736 NMR spectrum δ (CDCl ₃ ) ppm: 1.90 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.59 (2H, t, J = 7.5Hz), 3.62
(3H, s), 3.65 (3H, s), 5.65 (2H, d, J = 9Hz), 5.81 (2H, d, J = 9H
z), 6.68 (1H, d, J = 8Hz), 6.81 (1H, t, J = 7.5Hz), 6.97 (1H, dd,
J = 7.5,1.5Hz), 7.03 (2H, d, J = 8Hz), 7.09 (2H, d, J = 8Hz), 7.1
6-7.21 (1H, m), 7.19 (2H, d, J = 9Hz), 7.52 (2H, d, J = 9Hz)

Example 14 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (4-trifluoromethylphenyl) methyl] phenyl] butyrate Properties Colorless crystals (i-Pr ₂ O-MeOH) Melting point 105-106 ° C Elemental analysis value C ₂₅ H ₂₃ F ₃ ClNO ₄ S Theoretical value C _, 57.09; H , 4.41; N, 2.66 Experimental value C _, 57.01; H, 4.37; N, 2.51

Example 15 5- [4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenyl] methyl valerate Properties colorless liquid IR spectrum ν (liq) cm ^-1 : 3284, 1738 NMR spectrum δ (CDCl ₃ ) ppm: 1.50-1.73 (4H,
m), 2.33 (2H, t, J = 7Hz), 2.56 (2H, t, J = 7Hz), 3.66 (3H, s), 5.
21 (1H, d, J = 7.5Hz), 5.59 (1H, d, J = 7.5Hz), 6.98 (2H, d, J = 8.
5Hz), 7.01 (2H, d, J = 8.5Hz), 7.07-7.18 (2H, m), 7.18-7.23
(3H, m), 7.25 (2H, d, J = 8.5Hz), 7.54 (2H, d, J = 8.5Hz)

Example 16 Methyl (-)-4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyrate Methyl (+)-4- [4- (aminophenylmethyl) phenyl] butyrate 4. 28 g and triethylamine 2.5
To a solution of 3 ml of methylene chloride in 25 ml, 3.51 g of 4-chlorobenzenesulfonyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with diluted hydrochloric acid, aqueous potassium carbonate solution and water. After dehydrating the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to give colorless crystals (5.73 g).
Got Recrystallization from a mixed solution of ether and isopropyl ether gave colorless prism crystals having a melting point of 66.5 to 68 ° C. Elemental analysis C ₂₄ H ₂₄ ClNO ₄ S theory _{C, 62.94; H, 5.28;} N, 3.06 Found _{C, 63.01; H, 5.34;} N, 3.13 Specific rotation [α] _D ²⁰ - 8.3 ° (c = 1, MeOH)

Example 17 Methyl (+)-4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] butyrate In accordance with the method of Example 16, (-)-4- [4- (amino 4.25 g of colorless crystals was obtained from 3.05 g of methyl (phenylmethyl) phenyl] butyrate. Recrystallized from a mixed solution of ether and isopropyl ether, melting point 66-68.5 ° C.
Of colorless prism crystals were obtained. Elemental analysis value C ₂₄ H ₂₄ ClNO ₄ S theoretical value C _, 62.94; H, 5.28; N, 3.06 experimental value C _, 62.84; H, 5.30; N, 2.98 Specific optical rotation [α] _D ²⁰ + 8.3 ° (c = 1, MeOH)

EXAMPLE 18 Methyl 4- [4-[(4-fluorophenylsulfonylamino) phenylmethyl] phenyl] butyrate Methyl 4- [4- (aminophenylmethyl) phenyl] butyrate 2.50 g and triethylamine 1.35 ml A solution of 4-fluorobenzenesulfonyl chloride 1.72 g in methylene chloride 5 ml was added to a solution of methylene chloride 10 ml under ice cooling. The reaction solution was stirred at room temperature for 1 hour and then washed successively with diluted hydrochloric acid and water. After dehydrating the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 2.89 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3284, 1738 Mass spectrum m / z: 441 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.89 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.58 (2H, t, J = 7.5Hz), 3.66
(3H, s), 5.19 (2H, d, J = 7.5Hz), 5.59 (2H, d, J = 7.5Hz), 6.97
(2H, t, J = 8.5Hz), 7.01 (4H, s), 7.07-7.26 (5H, m), 7.63 (2H,
(dd, J = 8.5,5Hz)

According to the method of Example 18, Example 19
And 20 compounds were obtained.

Example 19 Methyl 4- [4-[(4-fluorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl] butyrate Properties Colorless plate crystals (i-Pr ₂ O-MeOH) Melting point 97-98 ℃ Elemental analysis C ₂₄ H ₂₃ F ₂ NO ₄ S Theoretical C _, 62.73; H, 5.05; N, 3.05 Experimental C _, 62.65; H, 5.14; N, 2.91

Example 20 Methyl 4- [4-[(4-chlorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl] butyrate Properties Colorless needle crystals (i-Pr ₂ O-MeOH) Melting point 107-108 ° C. Elemental analysis value C ₂₄ H ₂₃ ClFNO ₄ S theoretical value C _, 60.56; H, 4.87; N, 2.94 experimental value C _, 60.60; H, 4.82; N, 2.84

Example 21 4- [4-[(4-bromophenylsulfonylamino)
Methyl phenylmethyl] phenyl] butyrate To 2.00 g of methyl 4- [4- (aminophenylmethyl) phenyl] butyrate and 1.08 ml of triethylamine in 10 ml of methylene chloride, under ice cooling, 1.81 g of 4-bromobenzenesulfonyl chloride was added. A 5 ml solution of methylene chloride was added. The reaction solution was stirred at room temperature for 1 hour and then washed successively with diluted hydrochloric acid and water. After dehydrating the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to give 1.80 g of colorless crystals. Recrystallization from a mixed solution of diethyl ether and isopropyl ether gave colorless needle crystals having a melting point of 100.5 to 102 ° C. Elemental analysis value C ₂₄ H ₂₄ BrNO ₄ S theoretical value C _, 57.37; H, 4.81; N, 2.79 experimental value C _, 57.44; H, 4.80; N, 2.77

In accordance with the method of Example 21, Example 22
Was obtained.

Example 22 4- [4-[(4-bromophenylsulfonylamino)
(4-Fluorophenyl) methyl] phenyl] methyl butyrate Properties Colorless plate crystal (i-Pr ₂ O-MeOH) Melting point 93.5-94.5 ° C Elemental analysis value C ₂₄ H ₂₃ BrFNO ₄ S Theoretical value C _, 55.39 H, 4.45; N, 2.69 experimental value C _, 55.29; H, 4.56; N, 2.53

Example 23 4- [4-[(4-methylphenylsulfonylamino)
Methyl phenylmethyl] phenyl] butyrate To 2.00 g of methyl 4- [4- (aminophenylmethyl) phenyl] butyrate and 1.08 ml of triethylamine in 10 ml of methylene chloride was added p-toluenesulfonyl chloride 1.35 g of chloride under ice cooling. A 5 ml solution of methylene was added.
The reaction solution was stirred at room temperature for 1 hour and then washed successively with diluted hydrochloric acid and water. After dehydrating the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 2.28 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3284, 1736 Mass spectrum m / z: 437 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.89 (2H, qn, J =
7.5Hz), 2.30 (2H, t, J = 7.5Hz), 2.37 (3H, s), 2.57 (2H, t, J =
7.5Hz), 3.66 (3H, s), 5.07 (1H, d, J = 7Hz), 5.54 (1H, d, J = 7H
z), 7.00 (4H, s), 6.94-7.24 (7H, m), 7.55 (2H, d, J = 8.5Hz)

According to the method of Example 23, Example 24
Was obtained.

Example 24 Methyl 4- [4-[(4-fluorophenyl) (4-methylphenylsulfonylamino) methyl] phenyl] butyrate Properties Colorless plate crystals (i-Pr ₂ O-MeOH) Melting point 80-81 ℃ Elemental analysis C ₂₅ H ₂₆ FNO ₄ S theoretical C _, 65.91; H, 5.75; N, 3.07 experimental C _, 65.84; H, 5.90; N, 2.90

Example 25 Methyl 4- [4-[(4-methoxyphenylsulfonylamino) phenylmethyl] phenyl] butyrate Methyl 4- [4- (aminophenylmethyl) phenyl] butyrate 2.00 g and triethylamine 1.08 ml To a 10 ml solution of methylene chloride, a solution of 1.46 g of 4-methoxybenzenesulfonyl chloride in 5 ml of methylene chloride was added under ice cooling. The reaction solution was stirred at room temperature for 1 hour and then washed successively with diluted hydrochloric acid and water. After dehydrating the methylene chloride layer, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 1.90 g of a colorless liquid. IR spectrum ν (liq) cm ^-1 : 3288, 1736 Mass spectrum m / z: 453 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.89 (2H, qn, J =
7.5Hz), 2.29 (2H, t, J = 7.5Hz), 2.57 (2H, t, J = 7.5Hz), 3.66
(3H, s), 3.83 (3H, s), 5.07 (1H, d, J = 7Hz), 5.53 (1H, d, J = 7H
z), 6.79 (2H, d, J = 9Hz), 7.01 (4H, s), 7.07-7.24 (5H, m), 7.5
9 (2H, d, J = 9Hz)

According to the method of Example 25, Example 26
Was obtained.

Example 26 Methyl 4- [4-[(4-fluorophenyl) (4-methoxyphenylsulfonylamino) methyl] phenyl] butyrate Properties colorless plate crystals (i-Pr ₂ O-MeOH) melting point 81-82 Elemental analysis value C ₂₅ H ₂₆ FNO ₅ S theoretical value C _, 63.68; H, 5.56; N, 2.97 experimental value C _, 63.47; H, 5.71; N, 2.78

Example 27 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (2-thienyl) methyl] phenyl] butyrate 2.50 g of methyl 4- [4- [amino (2-thienyl) methyl] phenyl] butyrate and triethylamine 1.3
To a solution of 3 ml of methylene chloride in 25 ml, 1.82 g of 4-chlorobenzenesulfonyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with diluted hydrochloric acid, aqueous potassium carbonate solution and water. After the methylene chloride layer was dehydrated, the solvent was distilled off under reduced pressure to obtain 1.75 g of colorless crystals. Recrystallization from ethanol gave colorless prism crystals having a melting point of 115.5 to 117.5 ° C. Elemental analysis value C ₂₂ H ₂₂ ClNO ₄ S ₂ theoretical value C _, 56.95; H, 4.78; N, 3.02 experimental value C _, 56.87; H, 4.81; N, 3.06

Example 28 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (2-furyl) methyl] phenyl] butyrate 4- [4- [Amino (2-furyl) methyl] phenyl]
Methyl butyrate 0.90g and triethylamine 0.51ml
0.69 g of 4-chlorobenzenesulfonyl chloride was added to a solution of 10 ml of methylene chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with diluted hydrochloric acid, aqueous potassium carbonate solution and water. After the methylene chloride layer was dehydrated, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to give 0.60 g of colorless crystals. Recrystallization from a mixed solution of ethyl acetate and isopropyl ether gave colorless prism crystals having a melting point of 96-97.5 ° C. Elemental analysis value C ₂₂ H ₂₂ ClNO ₅ S theoretical value C _, 58.99; H, 4.95; N, 3.13 experimental value C _, 58.80; H, 4.84; N, 3.15

Example 29 4- [4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenyl] butyric acid 4- [4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenyl] methyl butyrate 2.70 g in methanol 7 ml solution 2N-sodium hydroxide aqueous solution 6 ml
Was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, water was added to the residue, the mixture was acidified with dilute hydrochloric acid, and then extracted with methylene chloride. After drying the methylene chloride layer, the solvent was distilled off under reduced pressure to obtain 2.10 g of colorless crystals. Recrystallized from a mixture of ethyl acetate and isopropyl ether to give a melting point of 153-15.
Colorless needle crystals were obtained at 5.5 ° C. Elemental analysis value C ₂₃ H ₂₂ ClNO ₄ S theoretical value C _, 62.23; H, 4.99; N, 3.16 experimental value C _, 62.10; H, 5.03; N, 2.97

Example 30 4- [Phenyl (phenylsulfonylamino) methyl]
Phenylacetic acid 4-[(phenylsulfonylamino) phenylmethyl]
To a solution of 1.80 g of methyl phenylacetate in 5 ml of methanol was added 4.6 ml of 2N-sodium hydroxide aqueous solution, and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was made acidic with diluted hydrochloric acid. The precipitated crystals were collected by filtration to obtain 1.42 g of colorless crystals. Recrystallized from ethyl acetate, melting point 1
Colorless needle crystals were obtained at 68 to 169 ° C. Elemental analysis value C ₂₁ H ₁₉ NO ₄ S theoretical value C _, 66.12; H, 5.02; N, 3.67 experimental value C _, 65.95; H, 5.07; N, 3.47

Example 31 4- [4-[(4-fluorophenyl) (phenylsulfonylamino) methyl] phenyl] butyric acid 4- [4-[(4-fluorophenyl) (phenylsulfonylamino) methyl] phenyl] butyric acid Methyl 1.50
3.4 ml of a 2N sodium hydroxide aqueous solution was added to 10 ml of a methanol solution of g, and the mixture was heated under reflux for 1 hour. The reaction solvent was evaporated under reduced pressure, water was added to the residue, the mixture was acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride layer was washed with water, dehydrated, and then the solvent was distilled off to obtain 1.64 g of colorless crystals. Recrystallization from a mixed solution of ethyl acetate-isopropyl ether gave colorless needle crystals having a melting point of 119 to 120 ° C. IR spectrum ν (liq) cm ^-1 : 3272, 1706 NMR spectrum δ (CDCl ₃ ) ppm: 1.90 (2H, qn, J =
7.5Hz), 2.34 (2H, t, J = 7.5Hz), 2.60 (2H, t, J = 7.5Hz), 5.23
(1H, d, J = 7Hz), 5.56 (1H, d, J = 7Hz), 6.89 (2H, t, J = 9Hz), 6.9
7 (2H, d, J = 8.5Hz), 7.02 (2H, d, J = 8.5Hz), 7.08 (2H, dd, J = 9,
5Hz), 7.35 (2H, t, J = 8Hz), 7.48 (1H, t, J = 8Hz), 7.67 (2H, dd,
(J = 8.5,1Hz)

The compounds of Examples 32 to 52 were obtained according to the methods of Examples 29 to 31.

Example 32 4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenylacetic acid Properties Colorless crystals (DMF-H ₂ O) Melting point 217-219 ° C. Elemental analysis value C ₂₁ H ₁₈ ClNO ₄ S Theoretical value C _, 60.65; H, 4.36; N, 3.37 Experimental value C _, 60.41; H, 4.56; N, 3.35

Example 33 3- [4- [phenyl (phenylsulfonylamino) methyl] phenyl] propionic acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 130.5-131.5 ° C. Elemental analysis value C ₂₂ H ₂₁ NO ₄ S theoretical value C _, 66.82; H, 5.35; N, 3.54 experimental value C _, 66.72; H, 5.40; N, 3.34

Example 34 3- [4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenyl] propionic acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 157 to 158.5 ° C Elemental analysis value C ₂₂ H ₂₀ ClNO ₄ S Theoretical value C _, 61.46; H, 4.69; N, 3.26 Experimental value C _, 61.30; H, 4.69; N, 3.02

Example 35 4- [4- [phenyl (phenylsulfonylamino) methyl] phenyl] butyric acid Property colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 131.5-132.5 ° C. Elemental analysis value C ₂₃ H ₂₃ NO ₄ S theoretical value C _, 67.46; H, 5.66; N, 3.42 experimental value C _, 67.54; H, 5.72; N, 3.15

Example 36 4- [4-[(4-chlorophenylsulfonylamino)
(2-Fluorophenyl) methyl] phenyl] butyric acid Properties Colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 128-129 ° C Elemental analysis value C ₂₃ H ₂₁ ClFNO ₄ S Theoretical value C _, 59.80; H, 4.58; N, 3.03 experimental value C _, 59.68; H, 4.54; N, 2.93

Example 37 4- [4-[(4-chlorophenylsulfonylamino)
(3-Fluorophenyl) methyl] phenyl] butyric acid Properties Colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 129-130 ° C Elemental analysis value C ₂₃ H ₂₁ ClFNO ₄ S Theoretical value C _, 59.80; H, 4.58; N, 3.03 experimental value C _, 59.74; H, 4.61; N, 2.96

Example 38 4- [4-[(4-chlorophenylsulfonylamino)
(4-Fluorophenyl) methyl] phenyl] butyric acid Properties Colorless crystals (AcOEt-i-Pr ₂ O) Melting point 169.5-170.5 ° C Elemental analysis value C ₂₃ H ₂₁ ClFNO ₄ S Theoretical value C _, 59.80; H, 4.58; N, 3.03 experimental value C _, 59.77; H, 4.58; N, 3.02

Example 39 4- [4-[(4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl] phenyl] butyric acid Property colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 152-153 ° C. Elemental analysis Value C ₂₃ H ₂₁ Cl ₂ NO ₄ S Theoretical value C _, 57.75; H, 4.42; N, 2.93 Experimental value C _, 57.79; H, 4.46; N, 2.81

Example 40 4- [4-[(4-chlorophenylsulfonylamino)
(4-Methylphenyl) methyl] phenyl] butyric acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 132.5-133.5 ° C. Elemental analysis value C ₂₄ H ₂₄ ClNO ₄ S Theoretical value C _, 62.94; H, 5.28; N, 3.06 experimental value C _, 62.93; H, 5.26; N, 3.02

Example 41 4- [4-[(4-chlorophenylsulfonylamino)
(2-Methoxyphenyl) methyl] phenyl] butyric acid Properties Colorless prismatic crystals (AcOEt-i-Pr ₂ O) Melting point 150.5 to 152 ° C Elemental analysis value C ₂₄ H ₂₄ ClNO ₅ S Theoretical value C _, 60.82; H, 5.10 N, 2.96 Experimental value C _, 60.76; H, 5.14; N, 2.82

Example 42 4- [4-[(4-chlorophenylsulfonylamino)
(4-Trifluoromethylphenyl) methyl] phenyl] butyric acid Properties Colorless crystals (AcOEt-i-Pr ₂ O) Melting point 157-159 ° C Elemental analysis C ₂₄ H ₂₁ ClF ₃ NO ₄ S Theoretical C _, 56.31; H, 4.13; N, 2.74 Experimental value C _, 56.26; H, 4.06; N, 2.67

Example 43 4- [4-[(4-Fluorophenylsulfonylamino) phenylmethyl] phenyl] butyric acid Properties Colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 122-123 ° C. Elemental analysis value C ₂₃ H ₂₂ FNO ₄ S theoretical value C _, 64.62; H, 5.19; N, 3.28 experimental value C _, 64.61; H, 5.23; N, 3.27

Example 44 4- [4-[(4-fluorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl] butyric acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 130-131 ° C. Elemental analysis value C ₂₃ H ₂₁ F ₂ NO ₄ S theoretical value C _, 62.01; H, 4.75; N, 3.14 experimental value C _, 62.23; H, 5.03; N, 2.98

Example 45 4- [4-[(4-chlorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl] butyric acid Property colorless crystal (AcOEt-i-Pr ₂ O) Melting point 140-141 ° C. Elemental analysis value C ₂₃ H ₂₁ ClFNO ₄ S theoretical value C _, 59.80; H, 4.58; N, 3.03 experimental value C _, 59.86; H, 4.58; N, 2.89

Example 46 4- [4-[(4-bromophenylsulfonylamino)
Phenylmethyl] phenyl] butyric acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 137 to 139.5 ° C Elemental analysis value C ₂₃ H ₂₂ BrNO ₄ S Theoretical value C _, 56.56; H, 4.54; N, 2.87 Experimental value C _, 56.37; H, 4.53; N, 2.82

Example 47 4- [4-[(4-bromophenylsulfonylamino)
(4-Fluorophenyl) methyl] phenyl] butyric acid Properties Colorless crystals (AcOEt-i-Pr ₂ O) Melting point 176-177 ° C Elemental analysis C ₂₃ H ₂₁ BrFNO ₄ S Theoretical C _, 54.55; H, 4.18; N, 2.77 Experimental value C _, 54.56; H, 4.24; N, 2.77

Example 48 4- [4-[(4-methylphenylsulfonylamino)
Phenylmethyl] phenyl] butyric acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 130.5-131.5 ° C Elemental analysis C ₂₄ H ₂₅ NO ₄ S Theoretical C _, 68.06; H, 5.95; N , 3.31 experimental value C _, 68.06; H, 5.97; N, 3.29

Example 49 4- [4-[(4-fluorophenyl) (4-methylphenylsulfonylamino) methyl] phenyl] butyric acid Properties Colorless crystals (AcOEt-i-Pr ₂ O) Melting point 85-86 ° C. Elemental analysis Value C ₂₄ H ₂₄ FNO ₄ S Theoretical value C _, 65.29; H, 5.48; N, 3.17 Experimental value C _, 65.28; H, 5.54; N, 3.16

Example 50 4- [4-[(4-methoxyphenylsulfonylamino) phenylmethyl] phenyl] butyric acid Property colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 118-118.5 ° C. Elemental analysis value C ₂₄ H ₂₅ NO ₅ S theoretical value C _, 65.58; H, 5.73; N, 3.19 experimental value C _, 65.52; H, 5.73; N, 3.19

Example 51 4- [4-[(4-fluorophenyl) (4-methoxyphenylsulfonylamino) methyl] phenyl] butyric acid Properties Colorless crystals (AcOEt-i-Pr ₂ O) Melting point 100-105 ° C. Elemental analysis Value C ₂₄ H ₂₄ FNO ₅ S Theoretical value C _, 63.01; H, 5.29; N, 3.06 Experimental value C _, 63.02; H, 5.26; N, 3.09

Example 52 5- [4-[(4-chlorophenylsulfonylamino)
Phenylmethyl] phenyl] valeric acid Properties colorless needle crystals (AcOEt-i-Pr ₂ O) Melting point 138.5 to 140 ° C Elemental analysis C ₂₄ H ₂₄ ClNO ₄ S Theoretical C _, 62.94; H, 5.28; N, 3.06 experimental value C _, 62.83; H, 5.27; N, 3.05

Example 53 (-)-4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenylbutyric acid (-)-4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenyl] Methyl butyrate 4.7
To a solution of 3 g of methanol in 50 ml, 13 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was heated at 50 ° C for 1.5 hours.
The reaction solvent was evaporated under reduced pressure, water was added to the residue, the mixture was acidified with diluted hydrochloric acid, and then extracted with methylene chloride. The methylene chloride layer was washed with water and dehydrated, and the solvent was distilled off under reduced pressure to give 4.36 g of colorless crystals.
Got Recrystallized from 75% methanol, melting point 13
A colorless prism crystal having a temperature of 5.5 to 137.5 ° C. was obtained. Elemental analysis C ₂₃ H ₂₂ ClNO ₄ S theory _{C, 62.23; H, 4.99;} N, 3.16 Found _{C, 62.21; H, 4.97;} N, 3.25 Specific rotation [α] _D ²⁰ - 9.3 ° (c = 1, MeOH)

Example 54 (+)-4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenylbutyric acid According to the method of Example 53, (+)-4- [4-[(4
-Chlorophenylsulfonylamino) phenylmethyl]
Phenyl] methyl butyrate 3.05 g, colorless crystals 2.8
8 g was obtained. Recrystallized from 80% methanol, melting point 1
Colorless crystals of 35 to 137.5 ° C were obtained. Elemental analysis C ₂₃ H ₂₂ ClNO ₄ S Theoretical value C _, 62.23; H, 4.99; N, 3.16 Experimental value C _, 62.11; H, 4.93; N, 3.14 Specific rotation [α] _D ²⁰ + 9.0 ° (c = 1, MeOH)

Example 55 (-)-4- [4-[(4-chlorophenylsulfonylamino) phenylmethyl] phenylbutyric acid 4- [4- (4-chlorophenylsulfonylamino) phenylmethyl] phenylbutyric acid 20.0 g and anhydrous Crystals precipitated from a solution of 17.8 g of brucine in 250 ml of methanol were recrystallized three times from methanol to give a melting point of 118-1.
7.29 g of colorless crystals at 21 ° C. were obtained. Elemental analysis value C ₂₃ H ₂₂ ClNO ₄ S ・ C ₂₃ H ₂₆ N ₂ O ₄
・ 2H ₂ O theoretical value C _, 63.18; H, 5.99; N, 4.81 experimental value C _, 63.25; H, 5.84; N, 4.79 Specific rotation [α] _D ²⁰ -24.4 ° (c = 1, MeOH) This crystal 6.88 g was added to a hydrochloric acid aqueous solution to give a free acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dehydrated, and then the solvent was distilled off to obtain 3.42 g of light brown crystals. 8
Recrystallized from 0% methanol, melting point 135-137 ° C
To obtain pale brown fine prism crystals. Elemental analysis C ₂₃ H ₂₂ ClNO ₄ S theory _{C, 62.23; H, 4.99;} N, 3.16 Found _{C, 62.20; H, 5.04;} N, 3.15 Specific rotation [α] _D ²⁰ - 9.1 ° (c = 1, MeOH)

Example 56 4- [4-[(4-chlorophenylsulfonylamino)
(2-thienyl) methyl] phenyl] butyric acid 4- [4-[(4-chlorophenylsulfonylamino)]
Methyl (2-thienyl) methyl] phenyl] butyrate 1.4
To a solution of 0 g of methanol in 20 ml, 8 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was acidified with diluted hydrochloric acid,
It was extracted with methylene chloride. The methylene chloride layer was washed with water and dehydrated, and then the solvent was distilled off under reduced pressure to obtain 1.05 g of colorless crystals. Recrystallization from a mixed solution of ethyl acetate and isopropyl ether gave colorless needle crystals having a melting point of 128 to 129.5 ° C. Elemental analysis value C ₂₁ H ₂₀ ClNO ₄ S ₂ theoretical value C _, 56.05; H, 4.48; N, 3.11 experimental value C _, 56.09; H, 4.49; N, 3.18

Example 57 4- [4-[(4-chlorophenylsulfonylamino)
(2-furyl) methyl] phenyl] butyric acid 4- [4-[(4-chlorophenylsulfonylamino)
Methyl (2-furyl) methyl] phenyl] butyrate 0.55
3 g of a 2N sodium hydroxide aqueous solution was added to a solution of g of methanol in 7.5 ml, and the mixture was stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was acidified with diluted hydrochloric acid,
It was extracted with methylene chloride. The methylene chloride layer was washed with water and dehydrated, and then the solvent was distilled off under reduced pressure to obtain 0.45 g of colorless crystals. Recrystallization from a mixed solution of ethyl acetate and isopropyl ether gave colorless crystals having a melting point of 141.5 to 142.5 ° C. Elemental analysis value C ₂₁ H ₂₀ ClNO ₅ S theoretical value C _, 58.13; H, 4.65; N, 3.23 experimental value C _, 58.09; H, 4.63; N, 3.21

Example 58 A tablet is produced by the following method. Compound of Example 29 50 mg Lactose Adequate amount Corn starch 34 mg Magnesium stearate 2 mg Hydroxypropyl methylcellulose 8 mg Polyethylene glycol 6000 0.5 mg Titanium oxide 0.5 mg ━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━ 160mg

Example 59 A capsule is prepared by the following method. Compound of Example 29 50 mg Lactose Appropriate amount Carboxymethylcellulose calcium 15 mg Hydroxypropylcellulose 2 mg Magnesium stearate 2 mg ━━━━━━━━━━━━━━━━━━━━━━━━━━━ 140 mg or more Mix by a conventional method and fill a hard capsule.

Example 60 A powder is manufactured by the following method. Compound of Example 29 50 mg Lactose Appropriate amount D-mannitol 500 mg Hydroxypropyl cellulose 5 mg Talc 2 mg ━━━━━━━━━━━━━━━━━━━━━━━━━━━ 1000 mg

Example 61 An injection is prepared by the following method. Compound of Example 29 10 mg Glucose 100 mg Sodium hydroxide qs Distilled water for injection qs ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 2 ml

[0182]

INDUSTRIAL APPLICABILITY The novel substituted benzenesulfonamide derivative represented by the above general formula (I) and the pharmacologically acceptable salt thereof produced as described above are a platelet aggregation inhibitor, an antithrombotic agent and an antithrombotic agent. It is extremely useful as an asthma drug.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location A61K 31/38 9360-4C C07D 307/52 333/20 (72) Inventor Tomio Suzuki Yoshida-gun, Fukui Prefecture Kamishibimura Otsuki 19-15

Claims (1)

[Claims] 1. The following general formula: (In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, R ² is a phenyl group which may have a substituent, a thienyl group or a furyl group, and R ³ is a hydrogen atom or A substituted benzenesulfonamide derivative represented by a lower alkyl group, and n is an integer of 1 to 5, and a pharmacologically acceptable salt thereof.